Project Summary Eukaryotic pathogens such as Leishmania are particularly challenging subjects of drug discovery efforts because their molecular machinery is structurally and mechanistically similar to our own, contributing to the risk of human drug toxicity. Our comparative genomic analyses indicate that the Leishmania protein synthesis machinery contains many unique and essential targets that differ substantially from their human counterparts. We will use a systems biological approach to build on preliminary findings and search for aminoacyl-tRNA- synthetase inhibitors with anti-leishmanial activity in a unique marine natural products library with proven efficacy against parasites. A high throughput screen will be implemented to generate preliminary leads, which will be validated in vitro and in vivo and used for testing in an established animal model for leishmaniasis. Such drugs could be used in a multidrug combination therapy, possibly with current anti-leishmanial agents, to exponentially reduce the probability of adaptive resistance. Because of our comparative systems biology approach, the proposed work will also be effective in identifying potential targets against other pathogenic kinetoplastids such as trypanosomes.